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By sequencing more people more thoroughly than ever before, researchers have affirmed that rare genetic variants — those carried by fewer than five people in a thousand — are widespread and likely to have an important role in human health.

Two studies published today in Science find that most human genetic variants are rare, and that rare variants are more likely than common ones to affect the structure or function of proteins, and therefore to have biological or medical consequences. The papers, along with another study published last week in Science, all conclude that humans carry such a high load of rare variants because the species experienced a population growth spurt that began a few millenia after the adoption of agriculture, which occurred about 10,000 years ago.
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Today’s papers come on the heels of a study published last week by Andy Clark and Alon Keinan of Cornell University in Ithaca, New York, that used data from sequencing studies to show that “explosive” growth of the human population beginning around 1,400 years ago helped to seed the human genome with variants that have not yet been weeded out by the process of natural selection.

Jonathan Pritchard, a population geneticist at the University of Chicago in Illinois, says that previous studies hadn’t been able to detect the excess of rare variation that would be expected to accompany the relatively recent surge in human population growth. “We’ve known that human populations are growing, but haven’t been able to see a clear signal of that” in genetic data, Pritchard says.“Now, with this very large sample size, it’s become easy to see the signal of recent population growth that has been difficult to find.”

This widespread rare variation means that it will be very complicated to follow through on the promise of initiatives such as the Human Genome Project: to find the genes that, when mutated, cause human disease, and to predict disease risk for an individual on the basis of his or her unique genetic profile. Akey and Bamshad, for instance, estimated that each person in their study carried between 25 and 31 genetic variants that were shared by no one else in the study. Predicting the effects of these rare variants will not be easy.
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The papers also indicate that researchers will need to study the genetic sequences of thousands of people — as many as 20,000 in some cases — to find enough of the variants to connect them to particular illnesses.

And, because many of the rare variants found in the studies were unique to specific populations with different geographic origins, variants linked to a particular disease risk in some groups won’t explain the same disease in others.

The abstract of one of the articles (by Mathew Nelson and co-workers) in Science carries a stark message:

Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (one every 17 bases) and geographically localized, such that even with large sample sizes, rare variant catalogs will be largely incomplete.

The other abstract, that of an article by Alon Keinan and Andrew Clarke, also from Science, is equally emphatic:

Human populations have experienced recent explosive growth, expanding by at least three orders of magnitude over the past 400 generations. This departure from equilibrium skews patterns of genetic variation and distorts basic principles of population genetics. We characterized the empirical signatures of explosive growth on the site frequency spectrum and found that the discrepancy in rare variant abundance across demographic modeling studies is mostly due to differences in sample size. Rapid recent growth increases the load of rare variants and is likely to play a role in the individual genetic burden of complex disease risk. Hence, the extreme recent human population growth needs to be taken into consideration in studying the genetics of complex diseases and traits.